Gut Symbiotic Microbes Imprint Intestinal Immune Cells with the Innate Receptor SLAMF4 Which Contributes to Gut Immune Protection Against Enteric Pathogens

Overview

Journal Gut

Specialty Gastroenterology

Date 2017 Mar 26

PMID 28341747

Citations 13

Authors

Allison Cabinian

Daniel Sinsimer

May Tang

Youngsoon Jang

Bongkum Choi

Yasmina Laouar

Amale Laouar

Affiliations

Soon will be listed here.

Abstract

Background: Interactions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field.

Aim: We have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is.

Methods: Expression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFP bone marrow chimaera mice, lymphotoxin α and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with and .

Results: SLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut-resident antigen-presenting cell (APC) are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death.

Conclusions: SLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut.

Citing Articles

Ligands for Intestinal Intraepithelial T Lymphocytes in Health and Disease.

Hada A, Xiao Z Pathogens. 2025; 14(2).

PMID: 40005486 PMC: 11858322. DOI: 10.3390/pathogens14020109.

Vitamin B produced by Cetobacterium somerae improves host resistance against pathogen infection through strengthening the interactions within gut microbiota.

Qi X, Zhang Y, Zhang Y, Luo F, Song K, Wang G Microbiome. 2023; 11(1):135.

PMID: 37322528 PMC: 10268390. DOI: 10.1186/s40168-023-01574-2.

Functional Foods: A Promising Strategy for Restoring Gut Microbiota Diversity Impacted by SARS-CoV-2 Variants.

Banerjee A, Somasundaram I, Das D, Jain Manoj S, Banu H, Mitta Suresh P Nutrients. 2023; 15(11).

PMID: 37299594 PMC: 10255361. DOI: 10.3390/nu15112631.

Blood-Brain Barrier Dysfunction in the Pathogenesis of Major Depressive Disorder.

Wu S, Yin Y, Du L Cell Mol Neurobiol. 2021; 42(8):2571-2591.

PMID: 34637015 PMC: 11421634. DOI: 10.1007/s10571-021-01153-9.

Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease.

Hanslik K, Marino K, Ulland T Front Cell Neurosci. 2021; 15:718324.

PMID: 34531726 PMC: 8439422. DOI: 10.3389/fncel.2021.718324.

References

Furusawa Y, Obata Y, Fukuda S, Endo T, Nakato G, Takahashi D . Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013; 504(7480):446-50. DOI: 10.1038/nature12721. View

Elishmereni M, Fyhrquist N, Gangwar R, Lehtimaki S, Alenius H, Levi-Schaffer F . Complex 2B4 regulation of mast cells and eosinophils in murine allergic inflammation. J Invest Dermatol. 2014; 134(12):2928-2937. DOI: 10.1038/jid.2014.280. View

Lee K, McNerney M, Stepp S, Mathew P, Schatzle J, Bennett M . 2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells. J Exp Med. 2004; 199(9):1245-54. PMC: 2211902. DOI: 10.1084/jem.20031989. View

Margraf-Schonfeld S, Bohm C, Watzl C . Glycosylation affects ligand binding and function of the activating natural killer cell receptor 2B4 (CD244) protein. J Biol Chem. 2011; 286(27):24142-9. PMC: 3129195. DOI: 10.1074/jbc.M111.225334. View

Yamagata T, Mathis D, Benoist C . Self-reactivity in thymic double-positive cells commits cells to a CD8 alpha alpha lineage with characteristics of innate immune cells. Nat Immunol. 2004; 5(6):597-605. DOI: 10.1038/ni1070. View

Georgoudaki A, Khodabandeh S, Puiac S, Persson C, Larsson M, Lind M . CD244 is expressed on dendritic cells and regulates their functions. Immunol Cell Biol. 2015; 93(6):581-90. DOI: 10.1038/icb.2014.124. View

Assarsson E, Kambayashi T, Schatzle J, Cramer S, von Bonin A, Jensen P . NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions. J Immunol. 2004; 173(1):174-80. DOI: 10.4049/jimmunol.173.1.174. View

Bida A, Upshaw Neff J, Dick C, Schoon R, Brickshawana A, Chini C . 2B4 utilizes ITAM-containing receptor complexes to initiate intracellular signaling and cytolysis. Mol Immunol. 2011; 48(9-10):1149-59. PMC: 3342820. DOI: 10.1016/j.molimm.2011.02.008. View

Tezuka H, Abe Y, Asano J, Sato T, Liu J, Iwata M . Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity. 2011; 34(2):247-57. DOI: 10.1016/j.immuni.2011.02.002. View

10.

Joseph J, Bunnachak D, BURKE T, Schrier R . A novel method of inducing and assuring total anoxia during in vitro studies of O2 deprivation injury. J Am Soc Nephrol. 1990; 1(5):837-40. DOI: 10.1681/ASN.V15837. View

11.

Pope C, Kim S, Marzo A, Masopust D, Williams K, Jiang J . Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection. J Immunol. 2001; 166(5):3402-9. DOI: 10.4049/jimmunol.166.5.3402. View

12.

Chlewicki L, Velikovsky C, Balakrishnan V, Mariuzza R, Kumar V . Molecular basis of the dual functions of 2B4 (CD244). J Immunol. 2008; 180(12):8159-67. DOI: 10.4049/jimmunol.180.12.8159. View

13.

McNerney M, Lee K, Kumar V . 2B4 (CD244) is a non-MHC binding receptor with multiple functions on natural killer cells and CD8+ T cells. Mol Immunol. 2004; 42(4):489-94. DOI: 10.1016/j.molimm.2004.07.032. View

14.

Killig M, Glatzer T, Romagnani C . Recognition strategies of group 3 innate lymphoid cells. Front Immunol. 2014; 5:142. PMC: 3978353. DOI: 10.3389/fimmu.2014.00142. View

15.

Schaefer B, Schaefer M, Kappler J, Marrack P, Kedl R . Observation of antigen-dependent CD8+ T-cell/ dendritic cell interactions in vivo. Cell Immunol. 2002; 214(2):110-22. DOI: 10.1006/cimm.2001.1895. View

16.

Wiggs L, Cavallaro J, Miller J . Evaluation of the oxyrase OxyPlate anaerobe incubation system. J Clin Microbiol. 2000; 38(2):499-507. PMC: 86133. DOI: 10.1128/JCM.38.2.499-507.2000. View

17.

FISCHER H, Reichmann G . Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol. 2001; 166(4):2717-26. DOI: 10.4049/jimmunol.166.4.2717. View

18.

Romero X, Benitez D, March S, Vilella R, Miralpeix M, Engel P . Differential expression of SAP and EAT-2-binding leukocyte cell-surface molecules CD84, CD150 (SLAM), CD229 (Ly9) and CD244 (2B4). Tissue Antigens. 2004; 64(2):132-44. DOI: 10.1111/j.1399-0039.2004.00247.x. View

19.

Graham A, Carr K, Sieve A, Indramohan M, Break T, Berg R . IL-22 production is regulated by IL-23 during Listeria monocytogenes infection but is not required for bacterial clearance or tissue protection. PLoS One. 2011; 6(2):e17171. PMC: 3039664. DOI: 10.1371/journal.pone.0017171. View

20.

Schuhmachers G, Ariizumi K, Mathew P, Bennett M, Kumar V, Takashima A . 2B4, a new member of the immunoglobulin gene superfamily, is expressed on murine dendritic epidermal T cells and plays a functional role in their killing of skin tumors. J Invest Dermatol. 1995; 105(4):592-6. DOI: 10.1111/1523-1747.ep12323533. View